Apoptosis is a major impediment to the development of malignancies. As tumors develop, cells encounter limitations in the availability of survival factors, oxygen, and nutrients, any of which is sufficient to directly trigger apoptosis. Hypoxia has been extensively studied as a promoter of metastasis in solid tumors and as an inducer of resistance to apoptosis. This is felt to be the reason that growth of solid tumors is angiogenesis-dependent. More recently, multiple myeloma has been recognized to also be dependent upon angiogenesis. Despite the initial focus on hypoxia as the trigger for angiogenesis, physiologic ischemia arising in the course of tumor progression results from the combined effects of low tissue concentrations of glucose and other metabolic substrates in addition to hypoxia. I have found that the mRNA for Bnip3, a proapoptotic BH3-only protein which has been shown to be induced by sustained hypoxia, is one of 19 out of 12,489 probesets significantly induced in the lymphoid cell line FL5.12 by a short period of hypoxia, when combined with sustained glucose withdrawal. Interestingly, Bnip3 is not induced by this short period of hypoxia alone. I hypothesize that Bnip3 and a highly homologous protein, Nix, function as sensors of the nutrient supply, removing cells which have outstripped their vascular supply by triggering mitochondrial apoptosis. This proposal describes a five year program to develop an academic career in hematologic malignancies and cancer biology. The experiments described in this proposal will provide valuable experience in the use and interpretation of a broad spectrum of molecular and cell biology techniques, including the generation and manipulation of murine genetic model systems under the mentorship of Dr. Craig Thompson. Dr. Thompson is the Chair of Cancer Biology at the University of Pennsylvania and has an extensive track record in mentoring clinician scientists along the path to highly productive research careers. This career development program will be enhanced by an advisory committee of experienced and highly regarded medical scientists who will provide both scientific and career advice. Overall, the time spent in the development of this project will allow the establishment of a line of inquiry in the fields of apoptosis and angiogenesis, and will provide the skills necessary to become a successful independent investigator.